This application is the resubmission for the competing continuation of a program project grant that was initiated in 1986. The proposed research is the outgrowth of the program's progress during the current funding period, and consists of three projects and two supporting cores, focused on the central theme of digitalis-induced signaling through the cardiac Na*7K+-ATPase. The participating investigators with expertise in membrane biochemistry, protein chemistry, molecular genetics, cell biology, and integrative cardiovascular physiology/ pharmacology will combine their efforts to conduct the following studies: Project I attempts to determine the molecular and cellular mechanisms by which the digitalis-induced activation of class 1A PI3K/Akt pathway leads to cardiac myocyte hypertrophy, and to assess if this seemingly benign hypertrophy is capable of antagonizing the deleterious effects of pathological hypertrophy and its consequences. Project 11 concentrates on the unraveling of the molecular interactions that constitute the formation of the Na+/K+- ATPase/Src complex, and on the evaluation of this complex as the receptor for the initiation of the multiple digitalis-induced signaling pathways and their functional consequences in the heart. Project III focuses on the established digitalis-induced communication between cardiac sarcolemmal Na+/K+-ATPase and ATPsensitive K+ channels of cardiac mitochondria, and proposes to determine the molecular and subcellular mechanisms of this communication, and the resulting digitalis-induced protection of the heart against ischemia-reperfusion injury. The core units are designed to provide administrative support and efficient management of the experimental animals and other shared resources of the program. These proposed studies are expected to expand knowledge on the newly appreciated physiological roles of cardiac NaVK4- ATPase, and to provide the bases for novel approaches to the prevention and treatment of ischemic heart disease and heart failure.